The structures of several Fab fragment-protein antigen complexes, shown by X-ray crystallography by others, have revealed the details of group contact in the antigen-antibody interface. However, despite such elucidation of the interacting groups, the antigen binding-interaction and the interaction mechanism responsible for the fine specificity are not well understood. For example, a combination of hydrophobic interaction, hydrogen bonds, electrostatic interaction and Van der Waals force is considered sufficient to describe the antigen-antibody interaction. In the studies of protein folding (see Project Z01DK25011-17 LCB) we have developed a model of a new non-covalent interaction, namely core loop interaction/core loop coalescence which drives folding. This core loop interaction is assumed to be sensitive to the detail of group contact by which the interaction is mediated. We have thought that such core loop interaction may be responsible for the fine specificity of antigen-antibody interaction. If this hypothesis is correct, antigen binding to antibody should stabilize the hydrophobic cores far from the antigen-binding site of antibodies. To test this hypothesis, we have measured amide hydrogen exchange rates of monoclonals 4-128-6, 4-74-6 and 2-96-12 to yeast iso-1- cytochrome c in the presence and absence of antigen. The amide hydrogen- deuterium exchange was followed by infrared spectrophotometry at pD 7.0,24- 25oC. Approximately 48 and 43 more mol of amide hydrogens per mol of antigen binding site, respectively of monoclonals 4-128-6 and 4-74-6 remained unexchanged after 48 and 72 h in the presence of antigen than in the presence of horse cytochrome c. Horse cytochrome c does not crossreact with these monoclonals. The results with monoclonal 2-96-12 has pointed to a novel aspect: both yeast iso-1 and tuna cytochromes c which have higher affinity to the monoclonal have decreased the hydrogen exchange rate more than horse cytochrome c which has lower affinity. These observations indicate that the core regions removed from the antigen-binding site of antibodies are stabilized by antigen-binding. In light of the core loop interaction theory it follows that the hydrophobic cores of VH and VL domains may influence the antigen-antibody interaction.